Chronic kidney disease (CKD) is grave health problem in the U.S.A. and worldwide with unacceptably high morbidity and mortality. Disorders of mineral metabolism are ubiquitous and assume a central role in CKD in terms of contribution to its progression, complications, and mortality. Models of dysfunctional mineral metabolism in CKD have evolved over time and some effective interventions have indeed been developed but are still rather limited in terms of their ability to prevent or reverse these morbid disorders. Based on the current database including our own preliminary data, we present a model where Klotho deficiency is an early event in CKD followed by rise in fibroblast growth factor-23 (FGF23) and decline in vitamin D, which is then compounded by hyperparathyroidism and hyperphosphatemia. These disturbances aggravate each other resulting in a self-amplifying downward spiral that leads to numerous morbid consequences of mineral disturbance that ramifies into bone disease and cardiovascular complications. We propose to test our hypothesis utilizing not observational measurements, but an interventional approach to interrupt the vicious cycle rather than using primarily rodent models of CKD. First, we will restore normal Klotho expression by replacement therapy and look for retardation or arrest of progression and complications of kidney disease. Second, we will suppress endogenous FGF23 using an antagonistic peptide (C-terminal fragment of FGF23) that we discovered and verified in normal rodents. The read-out will be the same as that used for testing Klotho replacement therapy. Third, we will test several simple maneuvers that can potentially preserve or stimulate endogenous Klotho expression. Depending on the initial findings from these three sets of studies, we will consider designing combination therapy. Mineral disturbances in CKD is in dire need for novel models that encompass more of our database and most critically, definitive interventions that target the root of the problem. The proposed experiments serve dual purposes. It will prove or refute our hypothesis of the vicious cycle of Klotho, FGF23, vitamin D, parathyroid hormone, and phosphate. In addition, it will also lay the foundation of preclinical data to test the therapeutic potential of Klotho replacement and FGF23 antagonism. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a formidable public healthy problem that impacts negatively on quality of life, survival, and health care costs but there is limited definitive therapy at present at our disposal. We constructed a model where abnormalities in two proteins called Klotho and Fibroblast Growth Factor-23 triggers a downhill spiral of a host of ill events in kidney disease. In this application, we aim to test this model and also devise novel ways to arrest this spiraling deterioration.